1. Field of the Invention
The present invention relates to certain 2',3'-dideoxy-5-substituted uridines and related compounds as agents for prevention and treatment of viral diseases, particularly HTLV-III/LAV, which causes acquired immunodeficiency syndrome (AIDS). The invention is also directed to a method of treatment of AIDS which involves treating the person afflicted with the disease with a composition including one or more of the compounds of the present invention.
2. Brief Description of the Background
AIDS was recognized as early as 1979. The number of cases reported to the Centers for Disease Control (CDC) increased dramatically each year since then, and in 1982 the CDC declared AIDS a new epidemic. Over 3,000 new cases were reported in 1984 alone. There are now close to 20,000 reported cases of AIDS, and approximately one half of those who have contracted the disease have died.
Retroviruses were proposed as the causative agent of AIDS. Two such retroviruses now known to cause AIDS have been identified and isolated: LAV (lymphadenopathy-associated virus) and HTLV-III (human T-cell leukemia virus). It was later determined that LAV and HTLV-III are identical. Antibodies to these viruses are present in over 80% of patients diagnosed as having AIDS or pre-AIDS syndrome, and they have also been found with high frequency in the identified risk groups.
There is considerable difficulty in diagnosing the risk of development of AIDS. AIDS is known to develop in at least 10% of the individuals infected with HTLV-III/LAV, although this percentage is suspected to be higher.
A patient is generally diagnosed as having AIDS when a previously healthy adult with an intact immune system acquires impaired T-cell immunity. The impaired immunity usually appears over a period of 18 months to 3 years. As a result of this impaired immunity, the patient becomes susceptible to opportunistic infections, various types of cancer such as Kaposi's sarcoma, and other disrders associated with reduced functioning of the immune system.
Another condition associated with HTLV-III/LAV is AIDS-related complex, or ARC. This condition is thought to lead to AIDS in some cases.
No treatment capable of preventing the disease or reversing the immunodeficiency of AIDS or ARC is currently available. All patients with opportunistic infections and approximately half of all patients with Kaposi's sarcoma have died within two years of diagnosis. Attempts at reviving the immune systems in patients with AIDS have been unsuccessful.
Recently, it has been reported that 3'-azido-3'-deoxythymidine (AzT) is an antiviral agent that inhibits the infectivity and cytopathic effect of HTLV-III/LAV in vitro. See Mitsuya, et al, Proc. Natl. Acad. Sci. USA 82, 7096-100 (1985). However, preliminary results indicate that this compound exhibits toxicity in a clinical setting. See Yarchoan et al, Lancet 575-580 (1986). AzT was originally synthesized by Horwitz et al., J. Org. Chem. 29, 2076-2078, 1964. Its activity against Friend leukemia virus (a retrovirus) was reported as early as 1973 (see Ostertag et al, Proc. Natl. Acad. Sci. USA 71, 4980-4985 (1974) and Krieg et al, Exptl. Cell. Res. 116, 21-29, 1978 and references cited therein). The compounds of this invention are structurally quite similar to AzT, but are remarkably less toxic to normal cells and mice.
In general, inhibitors of cellular processes will often limit viral replication, but these agents are usually quite toxic for the host as well. Most of the antiviral drugs that have been discovered so far cannot be prescribed because of their toxicity. For example, a compound structurally related to the compounds of the present invention, idoxuridine, is limited in clinical usefulness to topical application in ophthalmic solutions for treatments of herpetic keratitis because of its toxicity to normal cells. Clearly, there is a strong demand for new antiviral agents of low toxicity.
Various other workers have disclosed compounds which are structurally similar to those of the present invention, some of which are reported to be antiviral agents. Lin et al., J. Med. Chem. 26, 1691-1696 (1983) and Lin et al., J. Med. Chem. 26, 544-548 (1983) each disclose the synthesis and biological activity of various 3'-azido and 3'-amino analogs of pyrimidine dideoxyribonucleosides. However, none of the present compounds were synthesized or disclosed in these references. Furthermore, no mention was made in this reference of use of the compounds to treat retroviruses such as HTLV-III/LAV.
Krenitsky et al., J. Med. Chem. 26, 891-895 (1983) discloses some 3'-amino-2',3'-dideoxyribonucleosides of some pyrimidines. However, none of these compounds have the particular R.sub.5 substituents disclosed in the present invention. Furthermore, the HTLV-III/LAV is nowhere mentioned in this reference.
Some U.S. patents which disclose structurally related compounds, but which do not disclose any of the particular compounds of the present invention, include the following:
Eskstein, U.S. Pat. No. 4,331,662; Lin, U.S. Pat. No. 4,093,715; Greer, U.S. Pat. No. 4,210,638; Cook, U.S. Pat. No. 4,071,680; Verheyden I, U.S. Pan. No. 3,755,295; Bobek et al., U.S. Pat. No. 4,230,698; Lin et al., U.S. Pat. No. 4,128,639; Verheyden et al. II, U.S. Pat. No. 3,817,982; Verheyden et al. III, U.S. Pat. No. 3,687,931; Etzold, U.S. Pat. No. 3,775,397; and Verheyden IV, U.S. Pat. No. 3,282,921.
In view of the prior art, it is clear that there remains a strong need for new antiviral agents with low toxicity to normal cells. More particularly, because of the high mortality of AIDS and the lack of an effective treatment for this disease, there remains a great need for development of new low toxicity agents for such treatment. It was in this context that the present invention was achieved.